Known methods for producing R(-)-mandelic acid or derivatives thereof include: racemic resolution of chemically synthesized R,S-mandelic acid (racemic modification) by (1) fractional crystallization as described in JP-A-58-177933 (the term "JP-A" as used herein means an "unexamined published Japanese patent application); (2) chromatography as described in European Patent Publication No. 0 098 707A; and (3) conversion of the racemic modification into racemic esters followed by racemic resolution thereof by enzymatic asymmetric hydrolysis as described in K. Mori et al., Tetrahedron, 36, 91-96 (1980); and (4) chemical asymmetric synthesis with the use of a chiral reagent as described in D. A. Evans et al., J. Am. Chem. Soc., 107, 4346-4348 (1985). Biological methods therefor include the asymmetric hydrolysis of the abovementioned esters formed by process (3) above and (5) microbiological asymmetric reduction of benzoylformic acid as described in JP-A-57-198096; (6) hydrolysis of R(-)-mandelonitrile or substituted derivatives thereof which are asymmetrically synthesized with the use of D-oxynitrilase as described in U.S. Pat. Nos. 4,859,784 and 5,008,192; and (7) asymmetric hydrolysis of mandelonitrile, mandelamide or substituted derivatives thereof with the use of microorganisms belonging to the genus Alcaligenes, Pseudomonas, Rhodopseudomonas, Corynebacterium, Acinetobacter, Bacillus, Mycobacterium, Rhodococcus or Candida as described in European Patent Publication No. 0 348 901A.
However, each of the racemic resolution methods (1) to (3) requires a complicated process and a decrease in the yield occurs in each step. In method (4), using a chiral reagent as a catalyst, an expensive chiral reagent is required and a product of high optical purity is almost impossible to obtain.
The above-mentioned biological methods also have some disadvantages. Namely, in method (5) it is difficult to synthesize the substrate for the asymmetric reduction of benzoylformic acid. It is further difficult to maintain the NADH-regeneration system. The D-oxynitrilase method (6) is merely a basic finding that an optically active substance is obtained. The asymmetric hydrolysis method (7) requires a post treatment of another optically active substance remaining after the completion of the hydrolysis. In addition, the above-mentioned European Patent Publication No. 0 348 901A contains no particular example of the production of a R(-)-mandelic acid derivative from a substituted derivative of mandelonitrile. Therefore, it is unknown whether an R(-)-mandelic acid derivative of a high optical purity can be efficiently obtained or not.
As described above, these known methods suffer from various problems. Thus, none of these known methods is an industrially advantageous method for producing R(-)-mandelic acid or derivatives thereof.
The present inventors conducted extensive investigations to establish a method for advantageously producing R(-)-mandelic acid on an industrial scale. As a result, the present inventors discovered that R,S,-mandelonitrile could be easily racemized through dissociation equilibrium into benzaldehyde and hydrogen cyanide in an almost neutral or basic aqueous medium, and that R,S-mandelonitrile or benzaldehyde and hydrogen cyanide could be directly converted into R(-)-mandelic acid in conjunction with this racemization system together with a microorganism capable of asymmetric hydrolysis of mandelonitrile. Based on these findings, they disclosed a process for producing R(-)-mandelic acid by using a microorganism belonging to the genus Pseudomonas, Alcaligenes, Acinetobacter or Caseobacter as described in European Patent Publication No. 0 449 648A and another process for producing R(-)-mandelic acid with the use of a microorganism belonging to the genus Nocardia, Bacillus, Brevibacterium or Aureobacterium as described in European Patent Publication No. 0 449 648A. Subsequently, they further applied the above-mentioned findings to substituted mandelonitrile derivatives and, as a result, proposed a process for producing R(-)-mandelic acid derivatives with the use of a microorganism belonging to the genus Aureobacterium, Pseudomonas, Caseobacter, Alcaligenes, Acinetobacter, Brevibacteriumn or Nocardia as described in European Patent Publication No. 0 449 648A.
However, the R-stereoselectivities of the hydrogenases produced by these bacteria are not always satisfactory and thus further evaluation has been required for the steroeselectivities.